The Principal Investigator in this proposal is an M.D., Ph.D. post-doctoral fellow subspecializing in endocrinology who is interested in becoming an independent translational genomics investigator. He plans to extend the findings of diabetes genetics research into the clinical arena, and thus contribute to understand the heterogeneity of type 2 diabetes (T2DM), the impact of common genetic variation on the development of diabetes and the role of an individual's genetic profile in therapeutic response. In order to do so, he is currently training in Dr. David Altshuler human genetics laboratory at the Massachusetts General Hospital (MGH), which has intellectual and technological ties to the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research. He is also sponsored by Dr. David Nathan, the head of the MGH Diabetes Center and an international leader in diabetes clinical trials. This proposal aims to study the role of common variation in genes encoding drug targets for T2DM. Type 2 diabetes is a polygenic disease, and recent evidence has implicated single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-gamma (PPARG, a target for thiazolidinediones) and the sulfonylurea receptor complex in the pathogenesis of the disease. A T2DM association of common variants in AMP kinase (a presumed drug target for metformin) has not been reported. During the initial phase of the project, the haplotype structure of the genes for the sulfonylurea receptor, its associated potassium channel and the five known subunits of AMP kinase will be elucidated. Haplotype tag SNPs will be tested for association with T2DM in several family-based and case-control panels totalling 7000 subjects. The role of any associated SNPs and the Pro12Ala variant in PPARG in the development of T2DM and the response to various drugs will be studied in the Diabetes Prevention Program patient sample. In collaboration with Dr. Deirdre Blake, the impact of genetic variation in the above genes on response to short-term therapy will be measured by studying multiple parameters of human beta cell function. Finally, whether variability in long-term response to hypoglycemic therapy can be observed in clinical practice will be determined in a clinical study. This proposal should serve as the foundation for a large pharmacogenomics trial designed to evaluate the feasibility of genetically-tailored therapy in T2DM.